Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1>C(#N)C>[Br-:1].[CH2:12]([C:9]1[CH:10]=[CH:11][C:6]([C:5]#[C:4][CH2:3][CH2:2][N+:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)=[CH:7][CH:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1ccc(C#CCCBr)cc1
Reactant: Cc1cccnc1
Solvent: CC#N
Product: CCCCc1ccc(C#CCC[n+]2cccc(C)c2)cc1
Product: [Br-]
Yield: 77 %

Procedure:
1-(4-Bromo-but-1-ynyl)-4-butyl-benzene (1 mmol) was added to a solution of 3-picoline (3 mmol) in acetonitrile, and the solution was refluxed for 24 hours. The acetonitrile was removed in a vacuum, and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no picoline was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (77%). 1HNMR R (300 MHz, CDCl3, ppm), 9.48 (s, 1H), 9.33 (d, J=6.6, 1H), 8.24 (d, J=7.2, 1H), 7.93 (dd, J=6.6, J=7.2, 1H), 7.16 (d, J=8.2, 2H), 7.06 (d, J=8.2, 2H), 5.21 (t, J=6.0, 2H), 3.26 (t, J=6.0, 2H), 2.59 (s, 3H), 2.56 (t, 2H), 1.49-1.59 (m 2H), 1.25-1.37 (m, 2H), 0.9 (t, J=7.2, 3H); 13CNMR, 145.70, 144.78, 143.64, 142.26, 138.98, 131.15, 128.32, 126.94, 118.92, 85.84, 82.45, 59.90, 35.45, 33.28, 22.81. 22.24, 18.71, 13.89.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH2:32][C@H:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]([OH:40])=[O:39]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][NH:32][C@@H:33]4[CH2:37][CH2:36][CH2:35][C@@H:34]4[C:38]([OH:40])=[O:39])=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: N[C@H]1CCC[C@H]1C(=O)O
Product: O=C(O)[C@H]1CCC[C@H]1NCc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (200 mg; 0.48 mmol) and (1R,2S)-2-aminocyclopentanecarboxylic acid (125 mg; 0.97 mmol), to give Example 177 as a white solid. 1H NMR: (TFA-d, 400 MHz) δ 10.08 (2H, d, J=6.0 Hz), 9.40 (2H, d, J=5.9 Hz), 9.18 (2H, d, J=7.9 Hz), 8.87 (1H, t, J=7.5 Hz), 8.79-8.66 (3H, m), 8.55 (1H, t, J=7.9 Hz), 8.28 (1H, t, J=9.3 Hz), 5.62 (1H, d, J=13.2 Hz), 5.48 (1H, d, J=13.3 Hz), 5.01-4.88 (1H, m), 4.49-4.37 (1H, m), 3.46-3.37 (1H, m), 3.36-3.25 (2H, m), 3.20-3.00 (2H, m), 2.97-2.89 (1H, m). LC/MS (Method C): 524 (M+H)+. HPLC (Method I) Rt 13.12 min (Purity: 96.4%).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][S:16]2(=[O:22])=[O:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.C(O)C>CN(C)C=O>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:4]([C:6]2[N:7]=[C:8]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][S:16]3(=[O:21])=[O:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1nc(N2CCCCS2(=O)=O)n(C)c(=O)c1O
Reactant: NCc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: CCO
Product: Cn1c(N2CCCCS2(=O)=O)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Yield: 83.9 %

Procedure:
A mixture of 2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (1.00 g, 3.02 mmol) and 4-fluorobenzylamine (1.31 g, 10.5 mmol) in a mixture of anhydrous ethyl alcohol (40 ml) and N,N-dimethylformamide (10 ml) was heated under reflux for 10 h. The solvent was then evaporated in vacuo and the residue was diluted with dichloromethane (500 ml). The organic phase was washed with 5% aqueous acetic acid, brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and recrystallization of the white solid obtained from dichloromethane and ethanol gave 1.04 g (84% yield) of the title amide as white crystals; mp 227–228° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 and 2.07 (2×1H, m, CH2), 2.28–2.43 (2H, m, CH2), 3.19–3.31 (2H, m, CH2), 3.64 (3H, s, NCH3), 3.6–3.8 (2H, m, CH2), 4.59 (2H, AB part of ABX system, JAB=14.9 Hz, Δν=36.1 Hz, JAX=6.6 Hz, JBX=5.8 Hz, NCH2), 7.06 (2H, m, aromatics), 7.31 (2H, m, aromatics), 7.52 (1H, broad NH). Anal. Calcd for C17H19FN4O5S: C 49.75, H 4.67, N 13.65. Found: C 49.67, H 4.63, N 13.77.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=1)=[C:7]([O:28][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:31])=[O:30])[CH:6]=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:55](O)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)(=O)C.O1CCCC1>[CH2:55]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:15][CH:14]=1)=[C:7]([O:28][S:29]([C:32]([F:34])([F:35])[F:33])(=[O:31])=[O:30])[CH:6]=[CH:5]2)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: OCc1ccccc1
Reactant: O=S(=O)(Oc1ccc2cc(O)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1)C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(Oc1ccc2cc(OCc3ccccc3)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
Combine trifluoromethanesulfonic acid 6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-yl ester (247 mg, 0.48 mmol), triphenylphosphine (190 mg, 0.725 mmol), benzyl alcohol (0.075 mL, 0.725 mmol) and tetrahydrofuran (5 mL) in a flask placed in an ice bath. Add diisopropyl azodicarboxylate (0.14 mL, 0.725-mmol), stir for 1 hour, warm to ambient temperature and stir for 30 minutes. Dilute with ethyl acetate and wash with 50% saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry with magnesium sulfate and remove solvent under vacuum. Chromatograph on silica gel with dichloromethane/methanol mixtures to give 213 mg of the title compound (73%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2([C:17](=[O:25])[NH:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[C:27]([O:31][C:32]([NH:34][C@@H:35]([CH2:39][C:40]1[S:41][CH:42]=[CH:43][CH:44]=1)[C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2([C:17](=[O:25])[NH:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:16][CH2:15][N:14]([C:36](=[O:37])[C@@H:35]([NH:34][C:32]([O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:33])[CH2:39][C:40]3[S:41][CH:42]=[CH:43][CH:44]=3)[CH2:13][CH2:12]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Reactant: COC(=O)c1ccc(CC2(C(=O)NC3CCCCC3)CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CC2(C(=O)NC3CCCCC3)CCN(C(=O)[C@H](Cc3cccs3)NC(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-cyclohexylcarbamoyl-piperidin-4-ylmethyl)-benzoic acid methyl ester (3.32 mmol; 1.19 g) in DMF (50 mL) was added (S)-2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid (3.32 mmol; 0.90 g), N,N-diisopropyl-N-ethylamine (6.64 mmol; 1.18 mL) and HBTU (4.32 mmol; 1.64 g), and the resulting mixture was stirred at room temperature overnight. Ethyl acetate (150 mL) was added, and the resulting solution was washed with a 1H hydrochloric acid solution (2×50 mL), and brine (50 mL). The organic phase was dried over magnesium sulfate, filtered, and evaporated. The residue was purified via flash column chromatography (eluent gradient: 0 to 10% methanol in dichloromethane) and the desired fractions were combined and evaporated to yield 4-[1-(2-(S)-tert-butoxycarbonylamino-3-thiophen-2-yl-propionyl)-4-cyclohexylcarbamoyl-piperidin-4-ylmethyl]-benzoic acid methyl ester. MS (ESI) m/z 612.13 [M+H]+.
Reaction SMILES: C(O)C.[OH-].[K+].[CH2:6]([SH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=1>O>[CH2:6]([S:13][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: SCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccnc1SCc1ccccc1
Temperature: 55 °C
Reaction time: 0.42 h
Yield: 37.4 %

Procedure:
To a stirred solution of 35 ml of ethanol, 1 ml of water, and 2.0 g (0.025 mole) of 85% KOH pellets was added 3.2 g (0.025 mole) of benzyl mercaptan. To this mixture was added 4 g (0.025 mole) of 2-chloro-3-nitropyridine. After complete addition (20 minutes), the reaction mixture was warmed to 55° C. and held at that temperature for 25 minutes. It was then allowed to cool to room temperature over the next hour. The solid was filtered off (KCl) and the ethanol was removed from the filtrate. The residue was treated with 40 ml of acetone by warming, cooling and then filtering to remove more KCl. The filtrate was evaporated to leave an oil which solidified. The solid was recrystallized from 40 ml of ethanol to give 2.3 g of crystals, having a melting point of 57-59° C. The infrared spectrum was consistent with the structure. A second crop of 1.3 g of impure product was also obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([OH:7])[NH:4][N:3]=1.[C:8]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:13]=CC=C[CH:9]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(O)(C)C>C(Cl)Cl>[CH:8]([O:7][C:5]1[NH:4][N:3]=[C:2]([NH2:1])[CH:6]=1)([CH3:13])[CH3:9]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Nc1cc(O)[nH]n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)Oc1cc(N)n[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The title compound may be prepared via the following procedure: To a suspension of 3-amino-5-hydroxypyrazole (0.50 mol) in CH2Cl2 is added triphenylphosphine (0.59 mol) and the resulting mixture is cooled to 0° C. Diisopropyl azodicarboxylate (0.59 mol) is added drop-wise over a period of 35 minutes (the temperature of the reaction mixture is kept below 2° C.) to give a suspension. The reaction mixture is then held at 0° C. for 1 hour. A precipitate may be observed after 30 minutes of the reaction. Isopropyl alcohol (1.25 mol) is then added drop-wise over a period of 30 minutes at 0° C. as the slurry thins considerably to give a suspension. The reaction mixture is then held at 0° C. for 1 hour. The reaction mixture is warmed slowly to ambient temperature and is then held at ambient temperature overnight. The reaction mixture is filtered to remove undissolved solids. The filtrate is dried (MgSO4) and concentrated under reduced pressure to give an oil. Purification by column chromatography (5%→10% MeOH in CH2Cl2) affords the title compound. (400 MHz, DMSO-d6) δ ppm 10.3 (br s, 1H), 4.84 (br s, 2H), 4.65 (s, 1H), 4.52 (m, 1H), 1.20 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=1[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:5]2.C([O-])(=O)C.[K+].[Br:32]Br.O>C(O)(=O)C>[Br:32][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:12]1[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=1[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:8]2
Reactant: BrBr
Reactant: CCCCC(=O)c1c(-c2ccc3cc(O)ccc3c2)oc2ccccc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(O)ccc3c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.6 %

Procedure:
To an ice-cooled mixture of 1-[2-(6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (1.59 g, 4.62 mmol) in glacial acetic acid (50 mL) was added potassium acetate (4.54 g, 46.2 mmol). The mixture was stirred at room temperature for 15 minutes and then chilled again in an ice bath. Bromine (0.27 mL, 5.3 mmol) in acetic acid (6 mL) was added dropwise. The mixture was stirred at room temperature for 15 minutes. It was poured into excess water and filtered. The precipitate was dissolved in ethyl acetate, with some warming, and dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to dryness to afford 1-[2-(5-bromo-6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone as a yellow solid (1.85 g), mp 171-172° C. Mass spectrum (+APCl, [M+H]+) m/z 423. 1HNMR (400 MHz, DMSO-d6): δ10.95 (s, 1H), 8.4 (d, 1H, J=1.7 Hz), 8.15 (d, 1H, J=9.0 Hz), 8.05-8.1 (m, 2H), 7.95 (dd, 1H, J=8.8 Hz and 2.0 Hz), 7.7-7.75 (m, 1H), 7.35-7.45 (m, 3H), 2.75 (t, 2H, J=7.3 Hz), 1.5-1.6 (m, 2H), 1.1-1.2 (m, 2H), and 0.7 ppm (t, 3H, J=7.3 Hz). Elemental Analysis for C23H19BrO3. 0.25 H2O: Calculated: C, 64.57; H, 4.59; N, 0.00. Found: C, 64.19; H, 4.26; N, 0.05.
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>ClCCl.O1CCCC1.C(OCC)(=O)C>[Si:14]([O:7][CH:3]1[CH2:4][CH2:5][CH2:6][CH:1]([OH:8])[CH2:2]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: OC1CCCC(O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCCC(O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a solution of 1,3-cyclohexanediol (cis and trans mixture, 25 g) and imidazole (8.8 g) in a mixture of dichloromethane (150 ml) and tetrahydrofuran (150 ml) was added dropwise a solution of tert-butyldimethylsilyl chloride (16.2 g) in a mixture of dichloromethane (40 ml) and tetrahydrofuran (40 ml) at 0° C. A reaction mixture was allowed to warm to ambient temperature and stirred overnight. Insoluble material was removed by filtration and mother liquor was concentrated under reduced pressure to give residue, which was dissolved in ethyl acetate (300 ml) and washed in turn with 1N-aqueous hydrochloric acid (100 ml), brine (100 ml), saturated sodium hydrogen carbonate in water (100 ml), and saturated sodium chloride in water, and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (500 ml) eluting in turn with 10% and 20% ethyl acetate in n-hexane to give 3-(tert-butyldimethylsilyl)oxy-1-cyclohexanol (cis and trans mixture) (12.52 g).
Reaction SMILES: N[C:2]1[C:3]([F:18])=[C:4]([C:9]2[C:10]([C:16]#[N:17])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:5]([F:8])=[CH:6][CH:7]=1.N([O-])=O.[Na+].[BrH:23]>O1CCOCC1.O.[Cu]Br>[Br:23][C:2]1[C:3]([F:18])=[C:4]([C:9]2[C:10]([C:16]#[N:17])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: Br
Reactant: N#Cc1cccc(F)c1-c1c(F)ccc(N)c1F
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cccc(F)c1-c1c(F)ccc(Br)c1F
Temperature: -5 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of 3′-amino-6,2′,6′-trifluorobiphenyl-2-carbonitrile (0.5136 g, 2.07 mmol) in hot 1,4dioxane (1 ml) was added 48% aqueous hydrobromic acid (7 ml) and the mixture was cooled to −5° C. before adding dropwise a solution of sodium nitrite (0.1657 g, 2.40 mmol) in water (0.5 ml) over 5 min so that the temperature did not rise above −4° C. The resulting mixture was stirred at −5 to 2° C. for 2 h before adding a cooled (5° C.) solution of copper(I) bromide (0.4452 g, 3.10 mmol) in 48% hydrobromic acid (3 ml). The mixture was stirred for 5 min then heated to 46° C. over 1 h. The mixture was cooled to ambient temperature, diluted with water (50 ml) and extracted with diethyl ether (2×30 ml). The combined organic extracts were washed with 10% aqueous ammonia (25 ml), then saturated aqueous NaCl (20 ml), dried (MgSO4), and evaporated in vacuo. Purification by chromatography (silica gel, 20% EtOAc/isohexane) gave 0.3790 g (59%) of 3′-bromo-6,2′,6′-trifluorobiphenyl-2-carbonitrile as a white solid.
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=4)[O:14][C:13]3=[O:26])[C:8]([C:27]3[CH:28]=[C:29]([CH2:35][CH2:36][C:37]([OH:39])=O)[CH:30]=[CH:31][C:32]=3[O:33][CH3:34])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:47].C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=4)[O:14][C:13]3=[O:26])[C:8]([C:27]3[CH:28]=[C:29]([CH2:35][CH2:36][C:37]([NH2:47])=[O:39])[CH:30]=[CH:31][C:32]=3[O:33][CH3:34])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(CCC(=O)O)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C)cc(C)c2)[C@@H]1C
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CCC(N)=O)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C)cc(C)c2)[C@@H]1C
Reaction time: 0.5 h

Procedure:
To a solution of 3-[3-(6-azetidin-1-yl-2-{[(4S,5R)-5-(3,5-dimethylphenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}pyridin-3-yl)-4-methoxyphenyl]propanoic acid (EXAMPLE 228) (8 mg, 0.014 mmol) in DCM (2 ml) was added oxalyl chloride (2M in DCM) (100 μl, 0.200 mmol) and a drop of DMF. The solution was stirred for 30 minutes, concentrated, dissolved in THF (2 ml), added ammonium hydroxide (50 μl, 0.360 mmol) and stirred overnight. The mixture was acidified with 50 μl of TFA, concentrated, dissolved in MeOH, filtered, and purified by RP HPLC to afford the title compound. Mass spectrum (ESI) 529.5. 1H NMR (500 MHz, CD3OD): δ 7.31 (d, J=8.3 Hz, 1H); 7.20 (dd, J=8.4, 2.3 Hz, 1H); 7.02 (s, 1H); 6.96 (s, 2H); 6.83 (s, 2H); 6.35 (d, J=8.4 Hz, 1H); 5.40 (d, J=8.5 Hz, 1H); 4.80-4.48 (m, 1H); 4.24-3.64 (m, 2H); 4.05 (t, J=7.4 Hz, 4H); 3.75 (s, 3H); 2.88 (m, 2H); 2.48 (m, 3H); 2.41 (m, 2H); 2.28 (s, 6H); 0.59 (m, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:33]=[CH:34][CH:35]=1)[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]#[N:32])=[CH:26][CH:25]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:36]([F:39])([F:38])[F:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:40]=[N+:41]=[N-:42].[Na+].[NH4+].[Cl-].O>CN(C=O)C>[C:2]1([C:1]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:35]=[CH:34][CH:33]=[C:21]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][C:31]5[NH:42][N:41]=[N:40][N:32]=5)=[CH:26][CH:25]=4)[CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:36]([F:38])([F:37])[F:39])=[O:8])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc(COc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccc(Cc3nnn[nH]3)cc2)c1
Reaction time: 48 h
Yield: 22 %

Procedure:
A solution of ([4-({3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]phenoxy}methyl) phenyl]acetonitrile) (0.52 g, 1.0 mmol), sodium azide (0.33 g, 5.0 mmol) and NH4Cl (0.27 g, 5 mmol) in DMF (30 ml) was heated to 125° C. After 48 hr, the reaction was cooled and poured into water. The aqueous layer was extracted with EtOAc, dried and concentrated. The product was purified by column chromatography (eluent 50% EtOAc/Hexane) to give the title compound as a foam (0.12 g, 22%); MS (ESI) m/z [M+H]+(566); 1H NMR (DMSO) δ 16.2 (s, 1H), 9.13 (s, 1H), 8.32 (d, 1H, J=6.7 Hz), 7.92 (d, 1H, J=8.4 Hz), 7.75 (t, 1H, J=7.8 Hz), 7.63 (d, 2H, J=8.4 Hz), 7.57-7.53 (m, 1H), 7.39-7.25 (m, 7H), 6.98-6.93 (m, 2H), 6.84 (d, 1H, J=8.2 Hz), 5.02-4.43 (m, 2H), 4.32 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:16]O>O>[OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cccnc1O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cccnc1O

Procedure:
To a solution of 2-hydroxynicotinic acid (3.0 g) in methanol 15 ml, 1 ml of concentrated sulfuric acid was added, and the reaction solution was heated to reflux for 2 hours. The reaction solution was cooled, then the solvent was distilled off under reduced pressure, and the residue obtained was diluted with water and extracted with chloroform. The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to afford the title compound as a pale pink solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][O:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:26](=[O:27])[CH2:25][O:24][CH3:23])[CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC(=O)Cl
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)N(C)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h

Procedure:
To a solution of 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester (0.42 g) in DCM (10 mL) was added triethylamine (0.30 mL) followed by methoxyacetyl chloride (0.20 mL). After stirring for 3 h the reaction mixture was then diluted with DCM, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 4-[(2-methoxy-acetyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (0.293 g). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N+:22]([O-:24])=[O:23])=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][OH:34].Cl>CN(C=O)C>[OH:34][CH2:33][CH2:32][N:9]1[C:8]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:7]([N+:22]([O-:24])=[O:23])[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: COc1ccc(-c2[nH]c(=O)c3cc(OC)ccc3c2[N+](=O)[O-])cc1
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2c([N+](=O)[O-])c3ccc(OC)cc3c(=O)n2CCO)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
In a 25-mL flask under argon, 7-methoxy-3-(4-methoxyphenyl)-4-nitroisoquinoline-1(2H)-one (compound D5, 150 mg, 0.46 mmol) is dissolved in 5 mL of DMF. Potassium carbonate (317 mg, 2.3 mmol) is then added. After stirring for 30 minutes, 2-bromoethanol (329 μl, 4.6 mmol) is added. Stirring is maintained for 24 hours at 50° C. Once returned to ambient temperature, the medium is neutralized with 20 mL of a 1N hydrochloric acid solution then extracted with 3×10 mL of ethyl acetate. The organic phases are washed with 3×10 ml of H2O, dried over MgSO4 and concentrated under vacuum. The residue obtained is chromatographed on a silica gel column using the cyclohexane-ethyl acetate mixture (60/40) as eluent in order to produce the expected 2-(2-hydroxyethyl)-7-methoxy-3-(4-methoxyphenyl)-4-nitroisoquinoline-1(2H)-one 68 (73 mg, 43%) in the form of a yellow solid.